Freeze-drying process and apparatus

ABSTRACT

A process and apparatus for freeze drying of liquid material in a vessel in which the vessels are moved automatically through various stages including loading vessels onto racks, washing vessels in an inverted position, sterilizing vessels and racks, filling vessels with a liquid material, rotating the vessels and the liquid material contained within each vessel at a speed that allows the liquid to form a shell against the inner surface of the vessel, subjecting the vessels and the liquid material contained therein to freezing conditions sufficient to freeze the material into the form of a shell and then moving the rack and the vessels containing the frozen material through a vacuum drying chamber in which the frozen liquid material is dried.

This application is the national phase of International ApplicationPCT/GB96/00597, filed Mar. 14, 1996, which designated the U.S.

The present invention relates to a novel freeze-drying (lyophilisacion)process. This process is particularly advantageous for freeze-dryingpharmaceutical products. The invention also includes the lyophilisedproducts produced by the process.

Freeze-drying or lyophilisation, is used generally to increase thestability and hence storage life of materials. As such it isparticularly useful where a material is known to be unstable or lessstable in aqueous solution, as is often the case with pharmaceuticalmaterials.

In its simplest form freeze-drying consists of freezing the aqueousmaterial in a vial and then subjecting the material to a vacuum anddrying.

The conventional method of freeze-drying is to load magazines full ofvials onto chilled shelves in a sealed freeze-drying chamber. The shelftemperature is then reduced to freeze the product. At the end of thefreezing period, the aqueous material is frozen as a plug at the bottomof the vial. The pressure in the chamber is then reduced andsimultaneously the shelves are heated thereby causing the frozen waterto sublime leaving a freeze-dried plug in the bottom of the vial (FIG.4A). The whole lyophilisation cycle normally can take 20 to 60 hours,depending on the product and size of vial.

The disadvantages of this conventional method are as follows:

a) the time taken to freeze-dry a product;

b) the freeze-drying process is batch rather than continuous;

c) except in very sophisticated automated installations, there mustnecessarily be human operators to load the trays of vials into thefreeze-drying chamber, which leaves the product open to contamination;

d) the process is energy intensive when the power consumption of theclean room is taken into account;

e) the freeze-drying apparatus is very expensive and takes up a largearea of space, which is necessarily very expensive because it must bemaintained clean or sterile to a high standard; and

f) the vials are subjected to a number of discontinuous handlingoperations such as high-speed in line filling, transfer to holdingtables, and transfer to and from trays.

These operations risk vial damage or contamination, create particles inthe clean area, and require operator supervision.

European patent EP-A-0048194 discloses a method of "shell-freezing"material such that the resulting lyophilised product forms a relativelythin coat or "shell" in the vial. In this method, the aqueous materialis placed a vial which is then rotated slowly on its side in a freezingbath. The shell-frozen product is then loaded into a conventionallyophilisation chamber and dried over a six hour cycle (page 7).

However, although this method allegedly results in a "shell frozen"material, distribution can be non-uniform. Also relatively longlyophilisation times may still be required. The above rolling methodalso suffers from other disadvantages, including:

a) it limits the amount of liquid that can be placed in the vial sinceabove a certain limit some liquid would pour out;

b) there is a risk of spillage in any event during the rolling process;

c) rolling in a liquid coolant may result in contamination by thecoolant;

d) such a rolling process may result in a less uniform shell (giving alonger drying time); and

e) a rolling process may result in a longer freezing time (compared tothe present invention).

U.S. Pat. No. 3,952,541 describes an apparatus for a freezing aqueoussolution or suspension which comprises a refrigerated tank which has atleast one plate, which carries the materials to be frozen, mounted on ashaft to rotate at about 10 to 20 revolutions per minute around the baseof the tank. The tank is adjustable to tilt at (for example) a 45°angle, and a fan mounted inside the roof of the tank blows cold airaround the refrigerated tank. Once the product is frozen, it appearsthat the vials would have to be transferred to a separate dryingchamber, for approximately 111/2 hours. The whole lyophilisation cycletakes 12 hours and the product obtained is of an internally concaveparaboloid form.

The disadvantages of this process is that the time is still long (12hours), the process must be operated batchwise and it is not capable ofhandling a large throughput of vials. Furthermore, when transferring thefrozen open product from the refrigerated tank to a drying chamber,there must apparently be human operator contact and the product must bemaintained in a frozen stage until transferred.

British patent no. 784784 discloses a freeze-drying process in whichvessels containing liquid material are subjected to a centrifugal forceat a low vacuum. The low vacuum causes the water to be released and theeffect of centrifuging helps suppress the formation of bubbles and frothas the liquid boils under reduced pressure. Both this step and thedrying step involve subjecting the vessel to traumatic operations whichcan cause particles in the clean area of the process, and disrupt thefinal product.

DE-C-967120 relates to a continuous freeze-drying process. Each vial iscarried in a guide capsule where it is rotated rapidly under vacuumconditions to freeze the substance in the vial. Thereafter the guidecapsule releases the vial into a drying chamber and returns to collectanother vial. The drying chamber is composed of a long winding heatedconduit in which the vials are rolled down under gravity in abuttingfashion. Disadvantages of this process, however, is firstly that thevials undergo a very traumatic journey in the drying chamber and willbang together generating contaminating particles and disrupting thefrozen product. Secondly, the throughput of the process is limited inthat only one vial at a time can enter the drying chamber when anothervial exits. Thirdly as the guide capsules are continually recycled, theycan result in a source of contamination.

In U.S. Pat. No. 3,203,108, liquid in a vial is frozen into the form ofa shell by rotating the vial at high speed. However the heater fordrying the product is attached to the spinner. Therefore both thefreezing and drying operations take place within the same chamber whichlimits the throughput of the process.

In FR-A-1259207 a bottle containing a liquid is rotated quickly undervacuum, and the liquid frozen as a shell. There is no mention of how orwhere the product is subsequently dried.

In U.S. Pat. No. 3,195,547 a bottle containing liquid is rotated quicklyin a bath of freezing liquid thereby freezing the liquid in the bottleas a shell. There is no mention of how or where the product issubsequently dried.

In U.S. Pat. No. 2,445,12 a series of containers with a shell of frozenmaterial are received into drying cabinets which emit infra-red rays todry the shell of frozen material. The drying cabinets are housed in adryer and the process is batch process in that the whole dryer must beloaded and unloaded after drying. This limits the throughput of thedryer.

Further freeze-drying processes are described in British patent nos.1199285 and 1370683, and U.S. Pat. No. 3,769,717.

It is an object of the present invention to obviate or mitigate at leastsome of the aforesaid disadvantages.

It is a further object of the invention to provide a lyophilisationprocess and apparatus with shorter cycle times than the aforementionedprior process and apparatus.

It is yet a further object of the invention to provide lyophilisationapparatus which can be housed in a smaller space than the conventionalfreeze-drying apparatus and preferably also negates the need for humanoperator contact at critical parts of the process so as to minimisehuman contamination of the product.

According to a first aspect of the present invention there is provided aprocess for carrying out freeze-drying which includes a freezing step ofrotating about the longitudinal axis the vessel containing the liquidmaterial to be freeze-dried at a speed not less than that require tomaintain the liquid in a shell of substantially uniform thicknessagainst the inner walls of the vessel by the action of centrifugal forcewhile subjecting the liquid material to freezing conditions sufficientto freeze the liquid material into the form of said shell.

Preferably the vials are rotated about their axes while held in thesubstantially horizontal position. This aids the achievement of an evendistribution of liquid around the interior of the vessel.

The apparatus for carrying out the process of the first aspect of theinvention, forms the second aspect of the invention. Accordingly thereis provided apparatus for quick freezing of a liquid material containedin a sterilised vessel for subsequent crying in such a manner that saidliquid material forms a shell of substantially uniform thickness on theinner walls of said vessel; said apparatus comprising: rotatablegripping means for holding the vessel and rotating it about itslongitudinal axis and capable of rotating at high speeds so as tomaintain the liquid material against the inner walls of the vessel bycentrifugal force; filling means for introducing the liquid materialinto the vessel; freezing means for freezing the liquid in the form of ashell of substantially uniform thickness against the inner walls of thevessel; and conveying means to move the next vessel or vessels intoposition for filling and freezing.

By gripping means we mean a means to hold the vessel steadfast while itis rotated about its longitudinal axis.

Preferably the liquid material is aqueous. By aqueous material we meanaqueous solutions, suspension or the like preferably of pharmaceuticalproducts such as antibiotics vaccine, organic chemical drugs, enzymes orserum. The invention, however, can be used for freeze-drying materialdissolved or suspended in a solvent other than water.

By substantially uniform thickness of shell we mean whereby thethickness varies less than about 5% of the average thickness from theupper to the lower and of the vessel. By this we mean to include theaverage thickness of the shell measured at the mid-point between anylocal peaks or troughs in the shell surface caused by e.g. fluid dynamicinteractions between the liquid and freezing gas during the freezingprocess.

The invention (of the first and second aspects) can be applied to largevessels of liquid material, but preferably the vessels are vials orother such small vessels, such as about 10 to 40 mm in diameter and aplurality of these vials are filled and frozen simultaneously. This isthe type of vessel used in the pharmaceutical industry to carry at leastone unit dose of drug. The drug is then reconstituted with water beforeadministering to the patient.

The uniformity of the shell thickness is a function of the angle of thevessel and the speed of rotation. It is preferable to rotate the vesselup to about 45° off the horizontal, most preferably in a substantiallyhorizontal position.

When the liquid material is introduced to the vessel while it issimultaneously rotating substantially about the horizontal (or up toabout 45° off the horizontal), a shell frozen product is obtained withsubstantially no frozen product on the base of the vessel. This appearsto be the first time that this type of shell has been achieved, and itforms a third aspect of the invention. All shell dried productobtainable by the process and apparatus of the inventions also form thisfurther aspect of the invention.

The speed of rotation of the vessel should be controlled to maintain theliquid material in a shell on the inner walls of the vessel by theaction of centrifugal force. If the speed of rotation is too low theliquid material will not be held as a shell on the walls of the vessel.The speed of rotation is a design consideration depending on the densityof the liquid material to be frozen and the size of the vessel andpreferably about 2500 to 3500 revolutions per minute. Typically it willbe about 3000 revolutions per minute for a vial of about 10 to 40 mmdiameter.

It has also been found that if the liquid material is advantageouslyintroduced into the vessel while it is simultaneously rotating at anangle at or near the horizontal, then a greater quantity of material canbe introduced. That is, if a greater than the normal "fill" quantity ofmaterial is introduced when the vessel is stationary and horizontal,some material will run out. This is less likely to happen if the vesselis simultaneously rotating when it is filled.

The liquid material is frozen into the form of a shell by subjecting itto freezing conditions. In one preferred embodiment of the inventionthis is achieved by injecting a controlled flow of freezing inert gassuch as nitrogen into the vessel while it is simultaneously rotating thevessel. The flow of freezing gas is controlled in the sense that ifinjected at too high a pressure it may disrupt the shell of aqueousmaterial or may cause it to overflow.

Injecting freezing gas into the interior of the rotating vessel has theadvantage of speeding up the freezing step. Freezing gas could also,however, be circulated around the outside of the vessel, but with such aprocess it is important to minimise the points of contact between thegripping means and outer walls of the vessel so as to minimise anyinsulation of the liquid material by such contact.

The method of the present invention readily lends itself toincorporation in a continuous or semi-continuous freeze drying process.In such a process the vessels are held in racks or magazines and aremoved automatically through the various stages up to and including beingsubjected to the vacuum drying conditions.

A process for carrying out freeze-drying according to the first aspectof the invention includes a freezing step, said process including thefollowing steps:

a) loading one or more racks or magazines with the vessels to be filled;

b) washing the vessels, and racks or magazines;

c) sterilising the vessels, and racks or magazines;

d) filling the vessel with the liquid material to be frozen;

e) freezing the liquid material according to the first aspect of theinvention;

f) subjecting the vessels containing the frozen material to vacuumconditions;

g) drying the frozen material;

h) plugging the vessels; and

i) unloading the vessel and optionally capping and labelling thevessels.

In steps a) to c) and optionally in steps f) to h), the vessels canoptionally be held in an inverted position e.g. in the racks ormagazines. The vessels must be inverted in step b) so that washing waterwill drain. Furthermore, in a preferred embodiment of the inventionwhere the vessels are held by the base and gas injected in through theiropen necks, then having the vessels already inverted at step c) saves anadditional handling step.

It will be readily appreciated that the vessels could be unloaded priorto plugging.

A fourth aspect of the invention relates to the process for drying ashell dried material, and the fifth aspect relates to the apparatus forcarrying out this drying operation.

Accordingly in a fourth aspect of the invention there is provided aprocess for freeze-drying a liquid material frozen in the form of ashell on the inner walls of the body of a vessel, which includes thedrying step of applying heat for a time interval radially inwardly froma heating means to the shell in a vacuum chamber over a substantialsurface area other shell so as to dry the shell frozen material.

In a fifth aspect of the invention there is provided apparatus fordrying a liquid material frozen in the form of a shell on the innerwalls of the body of a vessel, said apparatus comprising:

a vacuum chamber,

heating means within the vacuum chamber designed to direct heat radiallyinwardly from the heating means to the shell frozen material, andconveying means to convey the vessel through the vacuum chamber.

The advantage of heating the vessel radially inwards from the heatingmeans is that the drying cycle time is greatly reduced as compared withconventionally drying methods. Here the base of the vessel is heated,such as on a heated shelf, and the heat transfer is axially upwardsthrough the glass walls of the vessel. This causes a temperaturedifferential along the length of the vessel walls, thereby causing a`drying front` in the shell frozen material. As a result the dryingcycle time is typically 30 hours for plug-frozen material compared to adrying cycle time in accordance with the invention of 3 hours.

Preferably the heating means is in close proximity to the wall of thevessel, such as 5 mm or less, advantageously 3 mm or less. In apreferred embodiment of the invention (heating blocks) the distancebetween the wall of the vessel and the heating means is about 1 mm.

Preferably also the heating means extends round substantially the wholecircumference of the vessel, and advantageously also extendssubstantially to the same height as the shell. In a particularlypreferred embodiment the heating means includes a heating chamber intowhich the vessel is received.

Since the drying time is greatly reduced, the throughput of the vacuumdrier is increased. Therefore a similar production capacity can beachieved with a much smaller vacuum drier than that used conventionally.

It will be appreciated that although the first, second or the fourth andfifth aspects of the invention can be used independently withconventional freezing or drying apparatus, it is advantageous to usethem together. Thus as a consequence of the decreased freezing timeachieved by the first and second aspects of the invention together withthe decreased drying time of the fourth and fifth aspects of theinvention, the production capacity of the conventional freeze-dryingapparatus can be achieved with much smaller apparatus according to theinvention. In fact the apparatus of the invention can be mobile, whereasconventional freeze-drying apparatus is much too large and bulky to bemobile. With all the aspects of the invention used together, anautomated continuous or semi-continuous process can also be designedwith minimal or no human operator contact. In this respect the conveyingmeans is preferably the arrangement of rollers described hereafter. Themagazine is also preferably of the design defined in the sixth aspect ofthe invention

Accordingly in a sixth aspect of the invention there is provided amagazine comprising a magazine comprising a tray having an upper andlower surface and having equispaced location apertures extending throughthe tray for locating the necks of the vials, each set of at least threelocating apertures defining an area therebetween in which an air flowaperture has been cut away, and one or more abutments adjacent eachaperture which trace the circumference of the base of a vessel about thevertical axis of the locating aperture to form a locating flange onwhich the vessel can be located in the upright position.

Preferably the location apertures are arranged in rows and columns andeach set of four location apertures define substantially the corners ofa square, in which an airflow aperture is provided.

All aspects of the invention will now be described by way of examplewith reference to the following drawings, in which:

FIG. 1 is a schematic cross-sectional side view showing the series ofsteps carried out in the continuous lyophilisation process of theinvention, including the filling and freezing of aqueous material in avial carried in a magazine and the drying of the material;

FIG. 2 is a schematic cross-sectional side view showing anotherembodiment of the process of the invention;

FIG. 3 is a top and side perspective view of the apparatus shownschematically in FIG. 1;

FIG. 4 is a cross-sectional view through a vial having a conventionalplug of lyophilised material at its base (4A), and a vial having a shellof lyophilised material on the inner walls of the vial in accordancewith the invention (4B);

FIG. 5 is a top perspective view of a magazine used in the process ofFIGS. 1 and 2;

FIG. 6 is a fragmented plan view showing a corner portion of themagazine displayed in FIG. 5;

FIG. 7 is a cross-sectional view through a portion of the magazine ofFIGS. 5 and 6 but showing a vial in position and a section of a rollerconveyor below the magazine;

FIG. 8 is a top and side perspective view of automated apparatusincluding an automated arm carrying grippers for carrying out thefilling and freezing steps D and E shown in FIGS. 1 and 2 (i.e. in theFill-Spin-Freeze (FSF) chamber);

FIG. 9 is a side view of the roller conveying means for carrying themagazines and vials throughout the process;

FIG. 10 is a plan view of part of the filling and freezing apparatusshown in FIG. 8;

FIG. 11 is a cross-sectional view of the grippers carried by the arm(not shown) of FIG. 8;

FIG. 12 is a schematic side view of the arm and grippers, butadditionally showing a driving means for rotating the grippers;

FIG. 13 is a schematic cross-sectional view of a portion of the arm andgrippers;

FIG. 14 is a cross-sectional view through a vial showing a nozzleinserted into the vial;

FIG. 15 is a schematic longitudinal cross-sectional view of the FSFchamber shown in FIG. 8;

FIG. 16 is another schematic plan view of a part of the filling andfreezing apparatus of FIG. 8, but additionally showing a check weighstation;

FIG. 17 is a top and side perspective view of the automated dryingapparatus for the drying step (H and I) shown in FIG. 1;

FIG. 18 is a cross-sectional plan view through a portion of a heatingblock used for drying the frozen material in the vials;

FIG. 19 is a cross-sectional plan view through heating walls which arean alternative embodiment to the blocks of FIG. 15 for drying the frozenmaterial in the vials; and

FIG. 20 is a plan view of the drying vacuum tunnel using the dryingapparatus.

Referring to the process of FIGS. 1 and 2, the steps of an embodiment-of the process and apparatus of the invention are as follows below.

Loading step (A): Vials (1) are loaded upside-down into a magazine (2),such that the neck of each vial locates in an aperture (3) of themagazine (2). This loading step (A) takes place in a non-sterileenvironment and the vials (1) can be manually or automatically loaded.The vial (1) are carried through the whole process in the magazine (2),which is in turn carried through the process on conveyor means in theform of roller conveyors (not shown in FIGS. 1 and 2, but shown in FIG.7). This is different from prior freeze-drying processes where the vialsare placed loosely on metal trays. The specifically designed magazines(2) are shown more particularly in FIGS. 5 to 7.

Washing step (B) and sterilizing step (C) The vials (1) are then washedboth inside and outside by injecting washing solution into the invertedvials (1) through their necks and spraying washing solution onto theoutside of the vials (1). The vials (1) are then hot air sterilized(Step C) by passing them into a sterilizing chamber (4--see FIG. 3))where hot air is blown onto the vials (1). The sterilized magazines (2)full of vials (1) are then carried by the conveying means onto aFill-Spin-Freeze (FSF) section (5) where the filling (D) and freezing(E) steps take place. The apparatus for carrying out these steps isshown more particularly in FIGS. 8 to 16.

Filling step (D) and Freezing step (E): In a filling and freezingoperation, the vials (1) and magazines (2) enter the FSF section (5) andare allowed to cool to the FSF internal temperature (typically about-50° C.). Vials (1) are removed from the magazines (2) one row at atime, (or feasibly two rows at a time) these being picked up by a robotarm (not shown in FIGS. 1 and 2) carrying a plurality of rotatablegripping means in the form of multi-fingered gripper (6). The vials (1)are rotated to horizontal and the robot arm swings 90° to the side ofthe FSF chamber. The vials (1) are rapidly rotated and filled with therequired dose of aqueous material, particularly a drug material such asa vaccine. Optionally the vials may be firstly filled then spun, butpreferably the filling occurs while simultaneously spinning the vial (1)The speed of rotation or spinning should be not less than that requiredto maintain the aqueous material in a shell (7) of substantially uniformthickness against the inner walls of the vial (1). The vials (1) arethen moved over nozzles from which is blown cold gas(typically--nitrogen at about -150° C.) to expose the spinning aqueousmaterial to freezing conditions sufficient to freeze the material intothe shell (7). The frozen shell (and later the dried shell) will be of asubstantially uniform thickness--i.e. the thickness of the shellmeasured at any position along the axis of the vial will not vary morethan about 5% providing that the thickness is measured as the averagebetween any surface peaks or troughs which may result from fluiddynamics during the freezing process. After a preset time to completefreezing, the spinning is stopped and the vials (1) returned to themagazine (2). The temperature of the interior of the enclosure ismaintained sufficiently cold so that the shells do not melt.

Weighing Step (F): Whilst a row of vials (1) is being filled and frozen,other vials (1) are weighed by indexing the magazine (2) back andforward over the weigh load cells (8--FIG. 1) This allows all vials (1)to be weighed before and after filling to check the correct dosage hasbeen dispensed. The weigh load cells (8) are shown more particularly inFIG. 16.

Turn over of vials (Step G): After filling and freezing, the vials (1)are (optionally) turned over from upside-down to the correct way up (seeFIG. 1). This is achieved by picking up the vials (1) (one row at atime) from one magazine (2) and transferring them to the magazine infront. A transfer arm (9) holding sufficient grippers for a row of vialsholds the vials (1) around their centre and rotates 180° about ahorizontal axis across the direction of movement of the magazine (2).The vials (1) are then released the correct way up on the magazine infront (2). This optional step demands that there is always theequivalent of an empty magazine in the process, which is loaded at thestart of production. In the process of FIG. 2, this turn over step doesnot occur and the vials are loaded inverted back into the magazine (2)before being conveyed onto the drying section of the process.

Vacuum Tunnel--Entry air Lock (Step H): Once the material in the vial(1) has been frozen, it is ready for drying. The magazine (2) enters anair lock chamber (10a) between the FSF chamber (4) and a vacuum dryingtunnel (11). The outer door (12a) of the airlock (10a) then closes andthe air pressure is reduced to the same as the vacuum tunnel (11). Theinner door (13a) then opens and the magazine (2) enters the vacuumchamber (11). The outer door (12a) is then opened ready for the nextmagazine (2).

The magazines (2) in the vacuum tunnel (11) move by conveyor means in anindexing motion one complete magazine length at a time, typically every10 mins. When the magazines (2) have been indexed to the new stationsheater blocks (14) lower over the vials (1). These direct heatsubstantially radially inwards to the vial over substantially the wholesurface area of the shell frozen material (7) and thereby provide theenergy to sublime off the water and freeze dry the material (7).Immediately prior to the magazines (2) indexing the heater blocks areraised to their first position to allow the magazine (2) and vials (1)to pass underneath and move one magazine (2) length to the next heaterblock (14). The heater blocks (14) are each set to a differenttemperature, so giving the temperature profile necessary to achieve thecorrect drying conditions for the particular drug material beinghandled. The freeze-dried shell material (7) produced according to theinvention is shown more clearly in FIG. 4B. The conventional plug driedproduct is shown in FIG. 4A.

At the end of the vacuum tunnel there is a second airlock. This works ina similar way to the input air lock, allowing the vials out whilstmaintaining the vacuum in the rain tunnel.

Plugging (Step J): There are two options for plugging. One is to carryout plugging in the outlet air lock (10b). In this case the plugs (15)would enter the air lock (10a) as a magazine (2) exits. The plugs (15)would be pushed into the vials (1) before opening the outer door (12b);this allows plugging at any desired pressure and in any chosen gas. Thesecond option is to plug after the air lock (10b) in a sterile pluggingarea (16) (see FIG. 3). Conventional equipment could be used here butthe size of the sterile area (16) would increase as a result.

Capping (step K): The crimping of caps (17) onto the plugs (15) coulduse standard equipment and be carried out in a clean (but notnecessarily sterile) area.

The whole freeze-drying process is operated from a central controlstation more particularly shown in FIG. 4.

FIGS. 5 to 7 show a magazine (2) used for carrying the vials (1) throughthe whole freeze-drying process. The magazine (2) of FIG. 5 comprises atray (18) having an upper and lower surface and having eight rows ofeight equispaced location apertures (19) extending through the tray (18)for locating the necks of the vials. Each set of four locating apertures(19) defines the four corners of a square in which an air flow aperture(20) has been cut away. A concave abutment (21) adjacent each aperturetrace the circumference of the base of a vial (1) about the verticalaxis of the locating aperture (19) to form a locating flange (22) onwhich vial (1) can be located in the upright position.

The vials (1) are preferably held in an inverted position as shown inFIG. 7. This Figure also shows that the top surface of the vial neckpreferably does not contact the magazine (2) so that any particles whichmay be produced by fretting between vial (1) and magazine (2) at point Aare unlikely to contaminate the inside of the vial (1).

The vial is supported on its neck at point B. This design depends uponthe diameter of the vial (1) being greater than the diameter of the neckof the vial.

The location aperture (19) in the magazine (2) is preferably castellatedas shown in FIG. 6. The castellations (23) allow water to be jettedbetween vial (1) and magazine (2) during the washing process to removeany particles that may have been trapped in the gap. The open area ofthe air-flow aperture (20) allows the free passage of air through themagazine during hot air sterilisation and for cold laminar air flow inthe FSF section (5) (see FIG. 15).

Locating holes (24) towards the outer edge of the magazine arepreferably provided for precise positioning. The holes are circular onone side and elongated on the other side to allow for position locationwithout overconstraint.

As shown more particularly in FIGS. 8 and 9, the means for conveying themagazines through the lyophilisation process preferably comprises aplurality of parallel rollers (25) axially mounted near both ends ofcorresponding rotatable shafts (26) which in turn are suspended betweentwo long parallel side supports (27). Referring to FIG. 7, each rollerhas an outwardly and circumferentially extending flange (28) on whichthe magazine rests and is moved along. Also mounted on the rotatableshaft (26) adjacent the roller is a toothed drive gear wheel (29). Theunderside of the magazine (2) has a rack with teeth (30) to engage withthe teeth of the drive gear (29) and index the magazine (2) along.

Through the whole process the magazine (2) is supported on a series ofthese rollers (25), not all of which have drive teeth. Furthermore notall of the drive teeth will move at the same time, thereby givingcontrolled indexing of the magazine throughout the process. For examplewithin the FSF chamber (5), the magazine (2) is preferably indexed byone row at a time, typically one row per minute. It will also move backand forward by one or two rows (as described hereafter) above the checkweighing cells (8). In the drying chamber (11), however the magazine (2)is preferably indexed by a whole magazine length at a time, one indexevery 8 minutes for example. Therefore the rollers in the FSF chamber(5) would not be directly linked to those in the drying chamber (11).The conveying rollers are however synchronised where necessary toprovide a smooth transfer between different roller sections.

FIG. 9 shows a side view of the drive roller arrangement transportingmagazines (2) through the process. More particularly, the figurerepresents the movement from the FSF region (5) to the airlock (10) andthe vacuum chamber (11) through air lock doors (12a and 13). In order tomove a magazine from region to region, each set of rollers needs to bedriven independently. The rollers (25) are connected together in groupsby drive shafts (31,32,33) and are driven by independent drive motors(34, 35 and 36). Each motor (34 to 36) is position controlled by centralsoftware to provide the necessary movements and to synchronise movementbetween adjacent groups during magazine transfer from group to group.

The transfer of magazine (2) and vials (1) throughout the process on thepreferred roller conveyor arrangement (25 to 36) of the invention has anumber of advantages for use particularly in a continuous freeze-dryingprocess. This is especially so in comparison with conventional driveswhich might be for example flat bed conveyors, chain link conveyors,other conveyor types or trays as used in conventional freeze drying.These are as follows:

1. There is no vial-to-vial contact. This reduces the amount of particlegeneration caused by fretting and reduces the chances of a vialfracture.

2. The magazine design is very open for the washing and sterilizingprocess. Washing is better because the exact vial location is knownhence wash jets can be directed at key parts of the vial. The openspaces of the magazine allow the hot air of sterilization to pass freelythrough the magazine.

3. The open structure also allows good airflow in the FSF region wheredownwards laminar air flow is needed to maintain very low particlelevels in the region of the vials. The layout of the supporting rollersis also clean and simple and hence helps air flow.

4. The magazines and rollers themselves constitute a greatly reducedsource of particles in comparison with conventional conveyors which tendto have large numbers of fretting surfaces.

5. Since the magazines preferably pass through the whole process (ratherthan short lengths of conveyors in each section) there is only a minimumof mechanical handling of the vials. There is no need for any vialhandling stage between the sterilizer and the FSF chamber for example,nor between the FSF and the drying chamber.

6. Since the magazines preferably pass through the whole process (ratherthan short lengths of conveyors in each section) they are repeatedlycleaned i.e. they are cleaned and sterilized on each path through,whereas a conveyor contained within any one machine element would not becleaned and hence would have the possibility to cause vial-to-vialcontamination.

7. The separate nature of the magazines allows them to pass through theair lock doors on entry to and exit from the tunnel. This is possiblebecause the air lock (sliding) doors can be located between two parallelrollers.

8. Since each vial is located in its individual location in themagazine, the vials can be readily located when necessary e.g. forgripping for the FSF process, for heating in the drying chamber and forplugging. Conventional vial transport generally requires a separatemechanism for vial alignment prior to handling stages.

9. Since each vial is located in its individual location in the magazineit can be individually tracked through the process for developmentpurposes or to identify a particular vial in the event of a processfailure such as poor filling. A vial which is identified by the checkweigh system as faulty, can therefore be subsequently retrieved at anyconvenient stage in the process.

Referring to FIG. 8 the magazines (2) and vials (1) are moved throughthe FSF chamber (S) in the direction of the arrow from the rear to thefront end thereof and then into the continuous vacuum dryingtunnel(consisting of the air locks (10a, 10b) and drying chamber (11)).

A robotic handler (37) is fixedly located towards the front end of theFSF chamber (S) and alongside the roller conveyor (25 to 36).

An arm (38) carrying a plurality of rotatable equispaced gripper means(39) extends perpendicularly from the upper end of the robotic handler(37) and is controlled thereby.

A filling (40) and freezing station (41) are both located in the chamber(5) alongside the roller conveyor (25 to 36) and rearwardly of therobotic handler (37). The filling station (40) consists of a row ofneedle nozzles (42) which each has a connector (43) for connectingoutside the FSF chamber to a reservoir of the aqueous material to belyophilized (44--see FIG. 9). The freezing station (41) also contains arow of needle nozzles (45) which also each has an adapter (46) forconnecting to a supply of freezing nitrogen gas (44) also outside theFSF chamber. The nozzles (42) of the freezing station (40) are locateddirectly below the nozzles (42) of the filling station (41) and bothsets of nozzles (42,45) are mounted on a casing (47) at approximatelythe same height as the arm (38). The filling and gas reservoirs (44) areconveniently located outside the FSF chamber (5) so that the FSF chamber(5) can be maintained as clean as possible (see FIG. 9). The fillingneedles (42) are provided with either heating means or thermalinsulation to prevent the liquid material freezing inside the needle(42) during filling.

FIG. 11 shows the rotatable vial gripper means (6) in cross-section. Thevial (1) is held in concentrically moving fingers (48) which aredesigned to hold the vial (1) with its axis accurately concentric withthe axis of rotation of the gripper (6). The fingers (48) are housed andare axially movable within an outer casing (49) and have outwardlyextending projections (50) which are slidably receivable intocomplimentary recesses (51) in the outer casing (49) or visa versa. Thevial (1) is spun to produce a shell (7) of the liquid drug inside thevial (1). The vial (1) is then transferred to a position enclosing thefreezing gas nozzle to freeze the shell (7). This ensures that thefrozen shell (7) has a substantially uniform wall thickness, and is animprovement over rolling while freezing. The fingers (48) are controlledby a push rod (52) extending axially along the gripper shaft (53)connected between the base of the fingers and a flange (55). The fingersare opened by the movement of an actuator frame (54) (which is mountedwithin the robot arm (37)) in the direction of the arrows against theflange (55) thereby compressing a spring (56) against the flange (55)and a second flange (not shown). In the open position the fingers (48)are pushed axially out of the outer casing (49) by the push rod (52)such that the projections (50) slide into the complimentary recesses(51) thereby allowing the fingers to open. In the closed position theforce of the spring (56) pulls the fingers (42) axially into the casing(43) and the projections (50) slide out from the recesses (51) therebyforcing the fingers (48) to close, as with a collet. This arrangementhas the advantage that in the event of power failure to the flangeactuator (53), the fingers (48) will remain clamped shut. In the openposition, the frame actuator (54) abuts the flange (55), but in theclosed position they are spaced apart allowing free rotation of thewhole gripping arrangement (6).

Each rotatable gripping means (6) is designed with a sufficientchamfered lead-in (57) that even a poorly shaped vial (1) located poorlyin a magazine will still move smoothly into the gripper means (6) whenit is lowered over the magazine.

FIG. 12 shows the drive arrangement (58,59) by which the gripping means(6) are all rotated. There is a single drive motor (58) linked to eachgripper shaft (53) by a toothed timing belt (59).

As shown more particularly in FIG. 13, since the FSF atmosphere is atabout -50° C., the robot arm (37) is covered by outer sleeve (60) whichhas internal insulation (61). The arm (37) is held at room temperatureby thermostatically controlled heater element (62). The outer sleeve(60) contains a sliding seal (63) to allow rotation and the robothandler (37) is provided with flexible bellows (64) to allow verticalmotion relative to magazine (2). This arrangement means that theinsulated outer sleeve (60,61) provides thermal insulation between thecold atmosphere and the relatively warm mechanical components of the arm(38).

The outer covering (60,61) of the arm (37) serves at least two purposes.

1. To allow the arm mechanisms to operate at room temperature while thearm is mounted within the FSF enclosure.

2. To protect the clean FSF environment from any particles which aregenerated by movable parts such as the spinning gripper shafts (53) orthe drive belt (59).

Air which is contained inside the enclosure will be extracted from theenclosure via vent aperture (64) and does not require any fan forextraction since the enclosure will be positively pressurised. Thisextraction will cause relatively high air velocity in the narrowaperture (65) between the spinning gripping means (6) and the outer armcasing (60), which will tend to carry any particles generated in thevicinity of the gripping means (6) together with any particles generatedwithin the interior atmosphere of the robot arm (37) towards the ventaperture (64) and hence away from the clean area of the vials (1).

In a fill, spin, freeze cycle, the arm (37) is lowered vertically from afirst position in which the gripping means (6) are disposedperpendicular to the roller conveyor (25 to 36) and spaced above thevials (1) carried thereon, and a second position in which each grippingmeans (6) grips the base of a vial (1) Typically one row of vials (1)are removed simultaneously from the magazine (2) The arm (37) is thenraised to the first position and rotated through 90° to a third positionin which the gripping means are substantially parallel to the rollerconveyor (25 to 36) and the vials (1) are held substantiallyhorizontally. The arm (37) then swings through 90° in a horizontal planein front of the filling means so that a nozzle (42) of the fillingstation (40) extends in through the neck of a corresponding vial (1).The vials are then rotated at a high speed of about 3000 rpm and ameasured dose of aqueous material is simultaneously injected into thevial (1), causing the material to be maintained in a shell (7) againstthe inner walls of the vial (1) by the action of centrifugal force. Thevials (1) are then withdrawn from the nozzles (42) of the fillingstation (40) and the arm (38) lowered to the height of the freezingstation (41) and moved towards it so that the nozzles (45) thereof areinserted into the vials (1) and a controlled jet of cold nitrogen gas(typically of a temperature of about -50° C.) is injected into the vial(1) whilst it is simultaneously rotating to freeze the aqueous materialinto a shell (7) against the inner walls of the vial (1). After a presettime to allow freezing (typically between 30 to 60 seconds) the rotationis stopped and the vials (1) returned to the magazine (2).

One major advantage deriving from the very short freezing cycle time isthat the throughput capacity of a conventional freeze-drying apparatuscan be accommodated on a much smaller scale of apparatus. As a resultthe process can be more easily automated and continuous therebyexcluding human operators from the process and thus maximizing thesterility of the process. To achieve this, the interior of the processline must be isolated from the exterior by `isolation technology`. Thisrequires both a barrier to the ingress of dirt or bacteria and alsomeans internally so that the chamber (4) can be cleaned and sterilizedautomatically--i.e. it must be cleared when sealed closed and it mustremain sealed throughout the whole production of a batch. Thereforepreferably the whole freeze-drying process of the invention is designedfor reliable mechanical handling. That is if a vial (1) is dropped or isbroken during the process then it is very hard to continue without anoperator going inside the isolator to tidy up. If this is necessary thensterility is lost, product in the area must be discarded and theprocedure for cleaning and sterilization must be repeated beforeproduction can continue. This would be a time consuming and costlydelay, and hence reliable mechanisms are important.

FIG. 15 shows how a sterile barrier is arranged in the FSF area (5). Thefigure is a cross section of the production line, looking in thedirection of product flow. The barrier itself (66) is shown as a thickwall because of the necessity for thermal insulation (internaltemperature may be -50° C.). The internal gas is circulated round by fan(67) in the direction of the various arrows. As the air passes throughfilter (`HEPA` filter) (68) fine particles and micro-organisms areremoved and the flow is also evened out so that the flow in the regionbelow the filter (68) is laminar, downwards. The downwards flow of cleanair ensures that the filling process and the waiting vials (1) are inclean air and that any particles shed in these or other regions arecarried downwards and clear of the vials.

The injection of the freezing gas to form the shell is shown moreparticularly in FIG. 14. Preferably the freezing nozzle (42) has aplurality of ports (69) along its length through which the freezing gasis injected.

The substantially horizontal orientation of the vial (1) mitigates theproblem of producing a parabolic surface to the shell and helps form ashell of substantially uniform thickness. The rate of heat transfer fromgas to product is increased by increasing the temperature difference (byhaving colder gas) and by increasing relative velocity between gas andliquid. Very high gas velocity however will disrupt the liquid shell andcause an uneven frozen shape. The pattern of ports (69) in the side ofthe nozzle (42) (FIG. 14) mitigates this problem by reducing any localpeaks in gas velocity.

Since the vial (1) can be simultaneously spun and filled it is possibleto fill the vial beyond the limit where the aqueous material would spillover the neck if the vials were not spinning. For sensitive drugs, itmay be advantageous to do the filling at a lower rotational speed thanthe freezing, to minimize the effect of shear.

It is advantageous to be able to weigh every vial (1) so that the weightof filled product in each vial can be checked and any process deviationsnoted and corrected. This means for example that if one of the fillingpumps was tending to fill slightly less than target fill weight then thepump could be adjusted to keep the fill weight under control. Any totalfilling failure for example caused by a blockage would be instantlyrecognized.

The weigh cells (8) are located in the FSF area (5) under one row ofvials adjacent to the robot arm (37) (FIG. 16). The weigh cells (8) aremounted on a frame (8A) such that when the frame (8A) is raised then allthe vials (1) in that row are lifted by the weigh cells (8) clear of themagazine (2) and their individual weights can be determined. Thedirection of magazine indexing is shown by the arrow.

The sequence of filling and weighing is as follows:

Row 1 is indexed over the weigh cells and is weighed, empty.

The robotic arm (38) then picks row 1, spin-fills and freezes it.

During this time the magazine (2) moves so that row 2 is indexed overthe weigh cells (8) and is weighed, empty.

Row 1 is then returned to the magazine (2).

The robotic arm (38) then picks row 2, spin-fills and freezes it.

During this time the magazine (2) moves so that row 3 is indexed overthe weigh cells (8) and is weighed, empty and then row 1 is indexed overthe weigh cells (8) and is weighed, full.

Row 2 is then returned to the magazine (2).

The robotic arm (32) then picks row 3, spin-fills and freezes it.

During this time the magazine moves so that row 4 is indexed over theweigh cells (8) and is weighed, empty and then row 2 is indexed over theweigh cells (8) and is weighed, full.

Row 3 is then returned to the magazine (2). This process is repeateduntil all vials (1) in the magazine (2) have been weighed and filled.The next magazine (2) is then indexed forward.

It is preferable that each vial (1) is weighed before and after fillingas described because the diference between fill weights that must bedetected is less than the likely difference in vial (1) weights.Preferably also each vial is weighed each time on the same weigh cell(8) so that variations between weigh cells (8) will have no effect onthe accuracy of the measurement.

Drying (Step I): The apparatus for drying the shell frozen material (7)is more particularly shown in FIGS. 17 to 20.

The vials (1) pass through the vacuum tunnel (10a, 10b, 11) from therear to the front. The vacuum tunnel (10a, 10b, 11) comprises a sealedvacuum drying chamber (11) and airlock chambers (10a, 10b) at the rearand front end of the drying chamber (11). Each airlock (10a, 10b) has aninner (13a, 13b) and outer (12a, 12b) door. The magazine (2) enters thefront air lock (10a) between the FSF chamber (5) and a vacuum dryingchamber (11). The outer door (12a) of the first airlock (10a) thencloses and the air pressure is reduced to the same as the vacuum dryingchambers (11). The inner door (13a) of the front airlock (10a) thenopens and the magazine (2) enters the vacuum drying chamber (11) Theinner door (13a) is then closed, the outer door (12a) of the frontairlock (10a) then opens ready for the next magazine (2)

A conveyor means (not shown) preferably of the same roller conveyorarrangement (25 to 36) in the FSF chamber (5) is provided for moving themagazines (2) of vials (1) through the vacuum tunnel (10a, 10b, 11) . Aseries of heater blocks (70) are spaced along the length of the vacuumchamber (11) above the conveyor means (25 to 36) and magazines (2). Asshown more particularly in FIG. 18 (which shows the plan view of aportion of a heater block (70) and vials), the heating blocks (70)comprise a plurality of tubular heating chambers (71) corresponding tothe number of vials (1) in each magazine (2). Each chamber (71) isdefined by a tubular wall (72) which extends to a height just above thetop of the vial (1), and the heating chamber (71) is optionally providedwith a top (72) which optionally may have an aperture (73) communicatingwith the drying chamber (11), to release water vapour from the chamber(71) (FIG. 1). In the embodiment of FIG. 2, there is no aperture in thetop of each heating chamber (71) but the vial (1) is inverted and watervapour escapes through the locating aperture (3) of the magazine (2).The lower end of each heating chamber is open to receive the vial (1).The heating blocks (70) are moveable vertically from a first positionabove the magazines (2) to a second position in which they are loweredso that the base of the heating block (70) rests on or near to the uppersurface of the magazine (2) such that each vial (1) fits snugly into aheating chamber (71) In the embodiment of FIG. 18, a small space is leftbetween the body of each vial (1) and the inner walls (72) of thecorresponding heating chamber (71). In this position heat can passradially inwards from the heating block to the shell frozen material (7)over a substantial area of the shell (7) in the direction of the arrows(FIG. 18). The heat is transferred by radiation and by conduction andconvection through the residual gas which exists in the (vacuum) heatingchamber (71). The vacuum space between the heating chamber wall (72) andthe body of the vial is important in that it has an effect on howefficient heat is transferred to the shell (7) of material. Preferablythe proximity of the heating wall and vial (1) is about 5 mm or less,more preferably about 3 mm or less. In the embodiment shown theproximate distance is about 1 mm.

The heater block (70) is constructed of a good thermally conductingmaterial. Aluminium, for example, is suitable providing it is treated toprevent the production of particles caused by surface oxidation forexample by anodising. The temperature of the heater block (70) can bemaintained by the passage of heating fluid through an element or pipe(73) attached to, or a conduit (73) running through the heating block(70).

Although the heating block (70) passes heat into the vials (1), it willsometimes be necessary for the block (70) to be cooled in order tomaintain correct temperature (if for example the heat gain from ambientto the block (70) is greater than the heat lost from the block (61) tothe vials (1). (Cooling is also needed at the start of a batch). Forthis reason the blocks (70) are controlled by a fluid which can beheated or cooled and not just by an electrical heater element. Inparticular during primary drying the vials (1) may be at -50° C. and theheater blocks at -20° C.

FIG. 19 shows an alternative heating means to the heating blocks (70) ofFIG. 18. In this embodiment long heating walls (74) are provided runningin parallel along each side of and down the middle (longitudinally) ofthe conveyor means (25 to 36) on which the magazines (2) rest. Each wall(74) is approximately the same height as the vials (1) when they areresting on the magazine (2). As with the heating blocks, the heatingwalls are preferably controlled by circulating a thermal liquid throughan element (73) running through or attached to the walls (74). The walls(74) consist of separate sections, the temperature of whichprogressively increases along the vacuum chamber (11) in the directionof the large arrow such that the temperature experienced by the shellfrozen material (7) in each vial (1) progressively increases as it movesaxially along the drying chamber (11). The thermal pathway for heattransfer is again radially inwards (as shown) by the arrows from theheating walls to the shell frozen material (3) over a substantial areaof the shell, thereby drying the shell (7) much quicker than previousmethods in the art. Again the heat transfer will be by a combination ofconduction or convection and radiation in the vacuum space between theheating walls (74) and the vials (1). As before the proximity betweenthe heating walls (74) and body of the vials is preferably 5 mm or less,more preferably about 3 mm or less.

The difference between the heating embodiments of FIGS. 18 and 19 isthat the vial (1) is passed between two heating walls (74) instead ofbeing received into a heating chamber (70). As a consequence, it is nolonger necessary to lift the heating blocks to allow the vials (1) tomove and therefore the embodiment of FIG. 19 lends itself to a moresimplified design. The disadvantage, however, is the longer thermalpathway and less efficient heat transfer from the heating walls (74) tothe shell (7). By substantially enclosing the vial with the heatingmeans, such as with the heating chamber (71) of the heating block (7), afaster drying time is achieved.

With both the heating block (70) and heating walls (74), because theheaters are individually temperature controlled, product passing alongthe tunnel are exposed to a drying cycle, such as for example: 1 hour at-25° C., 1/2 hour at +5° C., 1/2 hour at +5° C., 1/2 hour at +40° C.,and 1/2 hour at +40° C.,

FIG. 20 shows in plan view the arrangement of vacuum pumps andcondensers on the side of the vacuum chamber (11) and air locks (10a,10b). There is a separate vacuum pump (75) and condenser (76) for eachair lock (10a, 10b) and multiple vacuum pumps (75) are disposed alongthe length o: the tunnel. The vacuum will become progressively higheralong the length of the tunnel (10a, 10b, 11) as the product becomesprogressively more dry. Isolating doors (77) can therefore be providedat intermediate positions in the tunnel to isolate a vessel, if it isfound that product is sensitive to the degree of vacuum which is appliedduring secondary drying.

The condensers (76) will become progressively covered with ice as moreproduct passes down the tunnel. For the purpose of defrosting, theproduct on run can be interrupted but preferably there should be asurplus of condensing capacity such that each condenser (76) can beisolated by means of the valve (78) for defrosting after which time itcan be put back into service without interruption of production.

In both of the illustrated embodiments (FIGS. 18 and 19) of the heatingmeans (i.e. using the heating blocks (61) and heating walls (67)), theheat passes radially inwards from the heating means to the shell frozenmaterial in each vial. As a result the product is dried much quickerthan conventional drying apparatus where the vial rests on a heatedshelf (and thus only the base is heated directly). In this case heatpasses axially upwards from the base through the glass walls causing atemperature gradient that increases the time required to dry the shell(7). Furthermore, because of the efficient heat transfer conditions, thedrying process and apparatus of the invention is less energy demandingthan the previous process.

We claim:
 1. A process for carrying out freeze drying of liquid materialin a vessel, in which vessels are moved automatically through variousprocess stages up to and including being subjected to vacuum dryingconditions, said process stages comprising:(a) loading racks withvessels to be filled, such that said vessels are held apart atindividual locations in the racks, each said vessel comprising a vesselbase and a vessel wall having an outer surface and an inner surface; (b)washing the vessels and racks, said vessels being in an invertedposition so that washing water will drain therefrom; (c) sterilising thevessels and racks; (d) filling the vessels with liquid material to befrozen therein; (e) rotating the vessels containing the liquid materialto be frozen at a speed not less than that required to maintain theliquid in a shell of substantially uniform thickness against the innersurface of the vessel wall by the action of centifugal force whilesubjecting the liquid material to freezing conditions sufficient tofreeze the material as said shell, wherein vessels are removed from theracks and are rotated remote from the racks and after a preset time tocomplete freezing, the rotating is stopped and the vessels are returnedto the racks; and f) moving the racks with the vessels containing thematerial that has been frozen held at individual locations into andthrough a vacuum drying chamber to dry the material that has beenfrozen.
 2. A process as claimed in claim 1 wherein during stage (d), theliquid material is introduced into each vessel while the vessel isrotating, the rotation being maintained during stage (e).
 3. A processas claimed in claim 1 wherein during stage (e) each vessel is rotatedabout a longitudinal axis thereof while being held in a substantiallyhorizontal position.
 4. A process as claimed in claim 1 wherein theliquid material to be frozen is an aqueous drug and each vessel is avial of about 10 to 40 mm in diameter and carries at least one unit doseof drug.
 5. A process as claimed in claim 1 wherein during stage (e),said freezing conditions are achieved by injecting a freezing gas intoeach vessel.
 6. A process as claimed in claim 5 wherein the gas isnitrogen gas at about -50° C.
 7. A process as claimed in claim 1 whereinduring stage (e), the freezing conditions are maintained for 40 to 90seconds.
 8. A process as claimed in claim 1 wherein during stage (e),each vessel is rotated at about 2500 to about 3500 revolutions perminute.
 9. A process as claimed in claim 1 further including a firstweighing step wherein each vessel is weighed while empty in the rack anda second weighing step wherein each vessel is weighed after the materialhas been frozen therein, to check that a correct amount of material hasbeen frozen within the vessel.
 10. A process as claimed in claim 1wherein during stage (f), within the vacuum drying chamber, heat isapplied radially inwardly from a heater over a substantial surface areaof the shell of the material that has been frozen in each vessel.
 11. Aprocess as claimed in claim 10 wherein a distance between the heater andthe shell of the material that has been frozen is 5 mm or less.
 12. Aprocess as claimed in claim 1 wherein during stage (b) the vessels arewashed by injecting washing water up through the racks and into thevessels.
 13. A process as claimed in claim 1 wherein the vessels areloaded upside-down onto the rack in stage (a) so as to be disposed in aninverted position and are then subsequently washed and sterilised insaid inverted position.
 14. A process as claimed in claim 13 wherein thevessels are removed from the racks prior to stage (d) and returned tothe racks in said inverted position after stages (d) and (e), and arethen turned so as to be upside-up onto a rack before stage (f).
 15. Avessel having a vessel wall with an inner surface and an outer surfaceand having a lyophilised material formed as a shell on the inner surfaceof the vessel wall, said shell being produced by the process of claim 1.16. Apparatus for freeze-drying a liquid material contained in asterilised vessel having a vessel base and vessel wall with an innersurface and an outer surface so that said liquid material forms a shellof substantially uniform thickness on the inner surface of said vesselwall and in which a plurality of said vessels are moved automaticallythrough various process stages up to and including being subjected tovacuum drying conditions; said apparatus comprising:racks which includeindividual locations for locating vessels such that they are held apart;a washer for washing and a steriliser for sterilising the vessels andracks; rotatable grippers for removing the vessels from the racks andreturning the vessels to the racks, and for holding a vessel androtating said vessel about a longitudinal axis thereof at a high speedso as to maintain liquid material against the inner surface of thevessel wall by centrifugal force; filling means connected to a liquidmaterial supply for introducing liquid material into the vessel;freezing means for freezing the liquid material in the form of a shellof substantially uniform thickness against the inner surface of thevessel wall; a vacuum drying chamber containing a heater; and a conveyorto move racks holding the vessels containing the material that has beenfrozen into and through the vacuum drying chamber, and to movesubsequent racks loaded with vessels into position for filling andfreezing.
 17. Apparatus as claimed in claim 16 wherein the means forfreezing the liquid material includes an elongate nozzle cooperatingwith a connector for connecting to a gas supply, the nozzle beinginserted through a neck of each vessel while the vessel is rotating tointroduce the gas into the vessel.
 18. Apparatus as claimed in claim 17wherein the elongate nozzle is provided with a plurality of ports alonga length thereof through which the gas is injected.
 19. Apparatus asclaimed in claim 16 wherein the filling means is a filling nozzlecooperating with a connector for connecting to a liquid material supply,the filling nozzle being inserted through a neck of the vessel tointroduce liquid material into the vessel.
 20. Apparatus as claimed inclaim 16 which further includes a movable elongate arm located adjacentthe conveyor, filling means, and freezing means, said elongate armhaving a plurality of rotatable grippers equispaced along a lengththereof, said elongate arm being adapted to move a plurality of vesselsheld in the plurality of grippers from the conveyor to the filling meansand freezing means.
 21. Apparatus as claimed in claim 20 wherein theelongate arm is moveable vertically from a first position in which theplurality of grippers are substantially perpendicular to and spacedabove the conveyor, to a second position approximately one vessel lengthfrom the conveyor so as to take hold of a respective plurality ofvessels, and a third position adjacent the filling means and freezingmeans for filing the vessels with liquid material and freezing theliquid material in the vessels.
 22. Apparatus as claimed in claim 21wherein a robotic handler is coperably connected to the elongate arm tocontrol and move the arm, said handler being fixedly located adjacentthe conveyor, and filling means and freezing means such that the arm canswing through substantially 90° in a substantially horizontal planebetween said first position in which the arm and plurality of rotatablegrippers are substantially perpendicular to the conveyor and the thirdposition in which the elongate arm and rotatable grippers are disposedsubstantially parallel to and to the side of the conveyor and adjacentthe filling and freezing means ready for filling and freezing. 23.Apparatus as claimed in claim 16 wherein each of the plurality ofrotatable grippers comprises a drive shaft, an outer casing, fingersconnected to a base and axially movable into and out of said casing,resilient means, complementary projections and recesses provided on theouter wall of the fingers and on the inner wall of said casing, suchthat the fingers are moved axially outwardly of the casing in oppositionto the resilient means and said projections are received into saidrecesses thereby allowing the fingers to open and to release a vessel,and are moved inwardly of said casing by said resilient means, saidprojections and recesses sliding out of engagement thereby closing thefingers around a vessel.
 24. Apparatus as claimed in claim 22 whereinthe grippers is provided with a drive shaft and further including arotatable driver comprising a drive motor and a drive belt, said drivebelt extending round the drive shaft and drive motor so as to rotate thegripper.
 25. Apparatus as claimed in claim 16 wherein the conveyorcomprises parallel side support members;a plurality of parallel shaftssuspended between the support members; rotatable rollers mounted on theshafts to support the racks; and a driver to drive the racks along therollers.
 26. Apparatus as claimed in claim 25 wherein the driverincludes rotatable gear wheels mounted on shafts along the conveyor, soas to grip a base of the rack resting on the rollers and move the rackalong the conveyor.
 27. Apparatus as claimed in claim 16 wherein eachrack comprises a tray having upper and lower surfaces and havingequispaced location apertures extending through the tray for locatingthe vessels, at least one air flow aperture, and at least one abutmentadjacent each location aperture which trace a circumference of thevessel base about a vertical axis of the locating aperture to form alocating flange on which the vessel can be located in an uprightposition.
 28. Apparatus as claimed in claim 26 wherein teeth areprovided on the base of the rack for engaging with the gear wheels. 29.Apparatus as claimed in claim 16 wherein the heater within the vacuumdrying chamber directs heat radially inwardly from the heater to theshell of the material that has been frozen.
 30. Apparatus as claimed inclaim 29 wherein the heater is a heating block having at least oneheating chamber for receiving and extending substantially round thewhole circumference of the vessel, an inner wall of said heating chamberemitting heat radially inwardly to the shell of the material that hasbeen frozen.
 31. Apparatus as claimed in claim 29 wherein the heatercomprises a series of heating blocks, each maintained at a differenttemperature and spaced from one another along a length of the vacuumchamber, such that as racks of vessels are moved along the chamber bythe conveyor, the vessels are heated by successive heating blocks tosuccessively higher temperatures to thereby dry the shell of thematerial that has been frozen within the vessels.
 32. Apparatus asclaimed in claim 31 wherein the heater comprises parallel heated wallsextending substantially along a length of the conveyor and directingheat to the shell of the material that has been frozen such that theshell of material that has been frozen is dried as the racks with thevessels move along the conveyor between the heated walls.
 33. Apparatusas claimed in claim 29 wherein the heater has one of conduits extendingtherethrough and elements attached thereto for carrying a liquid tocontrol a temperature of the heater.
 34. Apparatus as claimed in claim29 wherein walls of the heater are at a distance of 5 mm or less fromthe outer surface of the vessel wall during a drying cycle.